Objective：The aim of the study was to explore the structure-activity relationship of PSD95-nNOS decoupling agent ZL006(1), and the mechanism of decoupling. Methods：Based on the PSD95-nNOS protein-protein interaction inhibitor ZL006 reported by our group, four series of 21 novel ZL006 derivatives were designed and synthesized by modifying its lipophilic part, linker and Salicylic acid structure. All the structures were confirmed by 1H NMR, 13C NMR and ESI-MS. Results：A comprehensive structure-activity analysis identified a potent inhibitor 23, with 54.34% cytoprotective activity @ 10 μmol/L in a LDH experiment on SH-SY5Y cells. At the same time, CCK8 assay showed these compounds displayed low toxicities against SH-SY5Y. Conclusion：This study not only enriches the diversity of chemical structures suitable for PSD95-nNOS protein-protein interaction but also provides a useful tool to further explore the neuroprotection therapeutic potential.